Effects of Mitochondrial Toxins on the Brain Amino Acid Concentrations

Abstract

In the pathogenesis of Parkinson's disease and Huntington's disease excitotoxicity may play an important role. The common toxin model for Parkinson's disease is MPTP, while for Huntington's disease it is 3-NP. These toxins inhibit the mitochondrial respiratory chain, resulting in an energy deficit. In the central nervous system, the amino acids act as neurotransmitters and neuromodulators. The energy deficit caused by these neurotoxins may alter the concentrations of amino acids. Thus, it can be claimed that the aminoacidergic neurotransmission can be changed by neurotoxins. To test this hypothesis we studied the amino acid concentrations in different brain regions following MPTP or 3-NP administration. The two toxins were found to produce similar changes. We detected marked decreases in most of the amino acid concentrations in the striatum and in the cortex, while the levels in the cerebellum increased significantly. The decreased amino acid levels can be explained by the reduced levels of ATP produced by these neurotoxins. In the cerebellum, where there is no detectable ATP loss, the elevated amino acid levels may reflect a compensation of the altered neurotransmission.

The Glycerophospho Metabolome and Its Influence on Amino Acid Homeostasis Revealed by Brain Metabolomics of GDE1(−/−) Mice

“…Subsequent targeted analysis using selected ion monitoring and a deuterated (d 3 )-serine standard confirmed the significance of this 1.6-fold decrease in serine in GDE1(-/-) brains (Figure 4A). Furthermore, the addition of d 3 -serine as an internal standard permitted precise quantitation of absolute serine concentrations, which were found to be approximately 1.6 μmols/g brain tissue in GDE1(+/+) mice, consistent with previous measurements (Klivenyi, et al, 2005; Nagata, et al, 1994). To evaluate the possibility that GroPSer serves as a metabolic precursor to serine in the brain, we compared the magnitude of the GroPSer elevation with the reduction in serine observed in GDE1(-/-) mice.…”

Pharmacological Therapy in Parkinson's Disease: Focus on Neuroprotection

“…Whatever the reason for and the specific mechanism of the mitochondrial dysfunction, it was hypothesized to cause neurodegeneration via one of the following pathways: (1) oxidative stress (see above), (2) energy depletion (that itself may cause cell death by activating K‐ATP channels [39], by compromising the proteasomal activity [40] or altering the neural amino acid levels [41]), and (3) the promotion of apoptosis (see below).…”

Promising therapeutic agents for the treatment of Parkinson’s disease

“…Protein aggregation, mitochondrial disturbances, oxidative stress, glutamate excitotoxicity, alterations of the tryptophan metabolism, immunological mechanisms, and genetic predisposition have all been suggested to play significant roles in the etiopathology of the disease [3][4][5][6][7][8][9][10][11][12][13] .…”